Dupilumab treatment increases transitional B cells in severe asthma
Authors: Marek Lommatzsch, Marieke Dost, Neeraja Jaishankar, Martin Weise, Paul Stoll, J. Christian Virchow, Kai Bratke
Journal: Allergy (2023)

To the Editor: The pathophysiology of asthmatic airway inflammation and the effects of biologics on T cell subsets and eosinophils in severe asthma are increasingly understood.1, 2 In contrast, there is little information on the effects of a treatment with biologics on B cells in severe asthma. Some B cell subsets such as memory B cells and plasma cells play a central role in IgE production and are, therefore, thought to have proinflammatory properties in allergic asthma.1, 3 However, growing evidence from animal models suggests immune regulatory (anti-inflammatory) functions of other B cell subsets.3-5 Immature B cells (also referred to as transitional B cells, TB cells) strongly express CD24 and CD38 during their maturation to antigen-naive B cells: these TB cells can have anti-inflammatory properties.3-5 However, the regulation of TB cells in severe asthma before and during treatment with biologics is unknown. It was the aim of this study to investigate the impact of the anti-interleukin-4-receptor alpha antibody dupilumab, which is known to reduce serum IgE levels,6 on circulating TB cells in patients with severe asthma, and to compare the observations with the effects of an antibody with a different mode of action, the anti-interleukin-5-receptor antibody benralizumab. In this single-centre study (Rostock, Germany), 20 patients with severe asthma and 20 controls without asthma (13 females) were analysed (Table 1). We included patients who were referred to our severe asthma outpatient clinic for evaluation of additional treatment options (see detailed patient inclusion criteria in the Data S1). Patients were assigned to benralizumab (30 mg s.c. every 4/8 weeks) or dupilumab (300 mg s.c. every 2 weeks) treatment according to the marketing authorisation criteria of the biologics and the choice of the treating physician (informed consent was obtained from all patients). Patients assigned to benralizumab (n = 10; seven females; all patients had adult-onset asthma; median of 5 exacerbations/year before benralizumab treatment) had higher median blood eosinophils, but lower median FeNO and serum IgE levels than patients assigned to dupilumab (n = 10; six females; six patients had adult-onset asthma; median of 3 exacerbations/year before dupilumab treatment; Table 1). One patient in the benralizumab group had allergies (against birch and mugwort), however, this patient reported only cutaneous reactions after allergen exposure. Thus, there was no patient in the benralizumab group reporting respiratory symptoms in conjunction with allergies. In contrast, three patients in the dupilumab group had allergies (patient 1: birch, grass, animals, mould; patient 2: birch, cat, grass; patient 3: birch, grass, house dust mites) in conjunction with respiratory symptoms suggesting that these allergies were related to the pathophysiology of their severe asthma. Total B cells and CD24++CD38++ TB cells in peripheral blood were analysed using flow cytometry (see methodology in the Data S1, including antibodies in Table S1 and gating strategy in Figure S1) at baseline, and after 1 and 6 months of treatment with the biologic. The percentages and total cell counts of B cell subpopulations in blood are detailed in the Data S1 (Tables S2 and S3). There were no differences in total B cells between controls and the benralizumab and dupilumab group, neither at baseline nor during treatment (Figure 1, Tables S2 and S3). At baseline, TB cell counts did not differ between controls and the benralizumab group, but there was a trend to decreased TB cells in the dupilumab group (Figure 1). After 6 months of benralizumab treatment, TB cells (Figure 1, Tables S2 and S3) and total IgE (Table 1) were unchanged, as compared with baseline. In contrast, there was a significant increase in the percentage of TB cells (Figure 1, Table S2) and in total TB cells (Table S3) and a decrease in total serum IgE (Table 1) after 6 months of dupilumab treatment. Taken together, we demonstrate, for the first time, that dupilumab treatment significantly increases blood TB cells in patients with severe asthma, an effect accompanied by a (well-established6) reduction in serum IgE concentrations. We hypothesise that inhibition of IL-4 and IL-13 might result in an increase in TB cells which in turn could suppress IgE production. This decrease in IgE levels could not only result in reduced allergic responses but may have also other beneficial effects on airway inflammation, unrelated to allergies.7, 8 It is important to note, however, that we did not assess functional properties of the TB cells and cannot quantify the exact amount of regulatory cells in the TB cell population and their effect on IgE production: further studies are, therefore, needed to clarify whether the observed increase in TB cells is associated with a suppression of IgE production. We speculate that low TB cell levels in conjunction with high IgE levels might predict a good clinical treatment effect of dupilumab in patients with severe asthma eligible for a treatment with biologics. In addition, unchanged TB cell levels in conjunction with an insufficient clinical response after 6 months of treatment might indicate that further treatment with dupilumab will not be promising. Subsequent and larger clinical trials (including assessment of functional B cell properties such as cytokine release in cell cultures) are needed to test these hypotheses. Of note, neither the increase in TB cells nor the decrease in serum IgE was observed during treatment with benralizumab, an anti-IL-5-receptor antibody. One possible reason for this observation might be the fact that the cytokines IL-4 and IL-13 are more involved in B cell maturation and IgE production than IL-5.4 Thus, blocking of IL-4 and IL-13, but not IL-5, could significantly impact on B cell maturation and IgE production. An additional reason could be the finding that there were higher IgE levels and more patients with allergies related to respiratory symptoms in the dupilumab group than in the benralizumab group. Thus, treatable IgE-related abnormalities might have been more prevalent in the dupilumab group than in the benralizumab group. We thank Anna Junge for her support. Land Mecklenburg-Vorpommern (Germany). None. Data S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.